Heritable Burden of Community Sudden Death by Autopsy and Molecular Phenotyping for Precision Genotype Correlation

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  FIGURE 1. Genetic Testing and Family Screening in the San Francisco POST SCD Study From February 1, 2011, to January 1, 2018 *World Health Organization definition of sudden cardiac death (SCD) (ie, presumed SCD) was employed: sudden and unexpected death within 1 hour of new symptom onset (witnessed), or within 24 hours of having been observed alive and symptom free (unwitnessed). aOf 306 cases that underwent genetic testing, 36 met high-suspicion phenotype criteria. bOf 18 high-suspicion cases that met with a genetic counselor, 17 had genetic testing. POST SCD = Postmortem Systematic Investigation of SCD study; y.o. = years old.

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  FIGURE 2. Pedigrees of HCM Cases Established With a Certified Genetic Counselor (A) Four-generation pedigree of 42-year-old male (III-1) who died of sudden arrhythmic death due to hypertrophic cardiomyopathy (HCM) with concordant pathogenic MYBPC3 variant with multiple family members affected by HCM (with same genotype) or sudden death. The father and uncle of the proband received implantable cardioverter-defibrillators (ICDs) with the latter subsequently receiving an appropriate ICD shock for ventricular fibrillation. (B) Four-generation pedigree of 59-year-old female (III-11) who died of sudden arrhythmic death and was found to have HCM with no pathogenic mutations detected. Patient had multiple relatives affected by HCM some with a concordant genotype, 3 of which carried a likely pathogenic mutation MYH7 that was not detected in the proband nor a first cousin with a clinical diagnosis of HCM. Based on the pedigree, a second variant was suspected to contribute to familial HCM. Family screening led to the implantation of 3 implantable cardioverter-defibrillators in this family. Symbols: Arrow = proband, squares = male sex, circles = female sex, diamonds = multiple individuals of both male…

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  CENTRAL ILLUSTRATION. Heritable Burden of Community Sudden Death by Autopsy and Molecular Phenotyping for Precision Genotype Correlation Autopsy phenotype: Of the 306 cases that were autopsied and underwent genetic testing, 62% had arrhythmic cause (eg, coronary artery disease, cardiomyopathy), 34% noncardiac cause (eg, occult overdose, intracranial hemorrhage), and 4% cardiac, nonarrhythmic cause (eg, heart failure, tamponade) of sudden death. High-suspicion phenotypes indicated by dashed box included premature coronary artery disease, hypertrophic cardiomyopathy, and primary electric disease, among others. Color denotes cause of death. Highlighting represents cases that were found to have an autosomal dominant or X-linked pathogenic likely/pathogenic (P/LP) variant. Genotype–autopsy correlation: Blood genotype–autopsy phenotype correlation with autopsy phenotype and cause of death. Apparent yield is the percent of cases with positive genetic testing irrespective of autopsy phenotype. Corrected yield is percent of cases with a P/LP variant concordant with cause of sudden death. Tissue investigation of genotype/phenotype discordance: Myocardial genotyping and expression studies to deeply evaluate…